Abstract Background Along with the aging population, the incidence of concomitant heart failure with preserved ejection fraction (HFpEF) and cancer, is increasing. However, little is known about the typical characteristics of patients with both HFpEF and a history of oncologic disease. Aim We aimed to characterize the distinctive characteristics and outcomes of patients with a history of cancer within a prospective HFpEF registry. Methods We analyzed data from 491 unselected HFpEF patients from our tertiary university center between 2010 and 2022 and followed the patients until 2023. Laboratory parameters and comorbidities were assessed. Patients were categorized into those with and without a history of cancer, including various malignancies, survivors of childhood cancer, radiation therapy, with or without chemotherapy. Kaplan-Meier estimates were used to explore the association between cancer history, as well as previous radiotherapy, and a combined endpoint of heart failure hospitalization and/or all-cause death. Results In this analysis of 491 HFpEF patients, a total of 101 patients (21%); had a history of cancer [mean age 74±7 years; female 72 (72%), male 29 (29%)]. The median time from cancer diagnosis to the initial HFpEF visit was 7.0 years (IQR 13-0.5 years). The most prevalent primary cancer sites included the chest wall (32%) comprising 4 adenocarcinomas of the lung and 28 cases of breast cancer, followed by the gastric (28%), urogenital system (18%), hematologic and lymphatic system (16%), cancers located at the head and neck (5%) and endocrine malignancies (1%). Radiotherapy (39%) and chemotherapy (26%) were common. Notably, no significant differences were observed, between patients with or without a history of cancer, in terms of median NT-proBNP levels [1037 (IQR 416-2075) vs. 1060 pg/ml (IQR 462-2013)] and the frequency of key cardiovascular comorbidities (all p>0.05, see Table 1). Over the study period [median follow-up 50 months (IQR 18-76)], 64 (64%) of cancer patients met the combined endpoint, with no statistically significant difference in outcomes between HFpEF patients with and without a cancer history (log-rank p=0.222, see Figure 1). Furthermore, there was no significant difference in the combined endpoint between patients who had undergone radiotherapy and those without (log-rank p=0.162). Conclusion Our findings highlight a high coexistence of cancer and HFpEF, which can frequently occur after oncology therapies. The data suggest that the presence of a history of cancer or previous radiotherapy did not significantly impact overall outcomes in HFpEF patients compared to those without cancer during the study period. Further research is needed to characterize patients with both disease entities in detail. Due to modern cardiovascular therapy in a university and cardio-oncology clinic setting, outcomes for cancer patients appear better than expected.